Tauroursodesoxycholic acid dihydrate is known to be useful in the treatment of biliary diseases (Italian Patent No. 1,197,330). The acid is prepared by reacting taurine in the form of an aqueous solution of an alkali metal salt thereof with the mixed anhydride of ursodesoxycholic acid. The latter acid is prepared by reacting ursodesoxycholic acid and an alkyl chloroformate, particularly methyl or ethyl chloroformate, in the presence of a tertiary base, such as triethylamine.
The preparation of tauroursodesoxycholic acid takes place in high yields and in an industrially advantageous manner, but the unpurified reaction product contains several by-products besides unreacted reactants (taurine and ursodesoxycholic acid) including, for example the tertiary amine, and chlorides originating from the hydrolysis of the unreacted alkylchloroformate. For therapeutic use of the compound, these impurities must be substantially removed, preferably without prejudicing the overall yield.
In the case of the sodium salt of conjugates with taurine and glycine of ketodesoxycholic acid (Hofmann A.F., Acta Chem. Scan. 17 (1963), 173-186), it is known to carry out the purification from the tertiary amine using a cationic resin. However, different steps and methods are foreseen for the removal of the other impurities (by-products and unreacted reactants), particularly steps involving solvent extractions and repeated crystallization.
In the case of tauroursodesoxycholic acid, the product of the conjugation is in fact the sodium salt of the acid. The free acid may be obtained from this according to standard methods of chemistry by adding a suitable acid, for example and preferably hydrochloric acid. Consequently salts, particularly chlorides, are still formed which are impurities and must be removed.
Even having recourse to subsequent crystallization, there remain in the product unacceptable amounts of impurities which, in view of the therapeutic use, make necessary further time-consuming and expensive purification steps. This is obviously disadvantageous for industrial scale production.
The present invention aims at solving the problem discussed above in an industrially acceptable and advantageous manner.